Chronic Lymphocytic Leukemia Treatment Options for Newly Diagnosed Patients

Individuals diagnosed with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) can have very different experiences and rates of disease progression. For many, the disease may progress slowly, while others will have a more aggressive course. There is also the possibility of developing complications related to autoimmunity or immunodeficiency, which are not related to disease progress. The current strategy involves deferring therapy until it is required. Thus, treatment often does not always immediately follow diagnosis. A strategy known as 'watch and wait' is an option when managing the disease.

Watch and Wait

The reason a doctor may advise observation, or 'watch and wait,' is that while the disease is progressing slowly, there are no studies that have shown that treatment administered early, while the patient is without symptoms, provides a benefit for the patient or an increased survival. Some people with CLL/SLL remain without symptoms for many years.

This strategy might seem counterintuitive. One might wonder why it is not better to treat when there are fewer sick cells around. The thing to remember is that treatment affects normal cells as well as cancer cells. Thus, there are advantages to limiting how much treatment a patient receives, especially early on.

Monitoring a patient's blood counts and routine physical examinations are very important elements of disease management during the watch and wait period. Treatment is usually recommended when a person:

  • is classified as Stage III or IV in the Rai classification system
  • develops symptomatic lymphadenopathy (swollen nodes)
  • develops so called B-symptoms (night sweats, low grade fevers, extreme fatigue)
  • has a doubling time of white count of less than six months
  • develops autoimmune findings (anemia – low red counts; thrombocytopenia – low platelets)

People with CLL/SLL are advised to talk with a doctor about whether their symptoms require treatment, balancing the benefits of treatment with side effects associated with the available treatments.

Recent advances in the understanding of certain genetic mutations and expressions and status of certain genes have some of the medical community (physicians and researchers) re-evaluating the 'watch and wait' policy. The healthcare community needs to determine whether earlier treatment would be of benefit to those patients with poor prognostic markers. Someone with poor chromosomal and genetic prognostic indicators may wish to discuss their options for the early treatment of their disease with their doctor. It is important to remember that even when comparing the survival curves for a bad prognostic marker versus a good one, the curves always overlap, and physicians do not know where an individual will be on the curve.

Types of Active Targeted Treatments

The treatment options available to a person diagnosed with CLL/SLL include: chemotherapy, biologic therapy, radiation, and stem cell transplantation.

Chemotherapy

Chemotherapy is the treatment of cancer with medication that circulates throughout the body. This treatment is especially helpful when the cancer in question is not localized to one organ of the body, as is the case with CLL/SLL. Two types of chemotherapy are most used in the treatment of CLL/SLL. These can be separated into two chemical groups known as nucleoside analogues and alkylating agents. The terms nucleoside and alkylating refer to the chemical structure of the compounds being used as chemotherapy. Both nucleoside analogues and alkylating agents attack cancerous cells, but are only partially selective in the process. They also attack other types of cells in the body and cause side effects. Side effects could be damage to the bone marrow, which produces normal cells, and as a result may include low white counts, decreased red blood cell counts, or also reduced platelet counts. These side effects are all called 'penias,' referring to "low." These "penias" include:

  • anemia (decreased red blood cell count, with decreased stamina and fatigue)
  • neutropenia (decreased neutrophils, one of the white blood cells which fight infection)
  • thrombocytopenia (decreased platelet count, with reduced ability for blood clotting)

You may hear your physician refer to these penias when you have a "complete blood count." Looking at these penias will help to carefully monitor the side effects of chemotherapy. Many medications exist to help you with these side effects.

The different chemotherapies used in the treatment of CLL/SLL are listed below.

Nucleoside (Purine) Analogues

One of the first drugs a person with CLL/SLL may receive is called fludarabine. Other nucleoside analogues, including pentostatin and cladribine are also sometimes used, although fludarabine is used more commonly. These are administered through an intravenous injection. They are listed below including their other common names:

  • Cladribine (2CDA, Leustatin)
  • Fludarabine (Fludara) thrombocytopenia (decreased platelet count, with reduced ability for blood clotting)
  • Pentostatin (Nipent, Deoxycoformycin)

Alkylating Agents

Some alkylating agents available for the treatment of CLL can be given orally, while cyclophosphamide may also be administered intravenously. Other agents are occasionally tried. Prednisone (available under many brand names) is a type of oral corticosteroid (a potent hormone) that is often given together with chlorambucil or cyclophosphamide. They are listed below including their other common names:

  • Chlorambucil (Leukeran)
  • Cyclophosphamide (Cytoxan, Neosar)
  • Bendamustine (Treanda) is a novel alkylating agent that damages the DNA in tumor cells, thereby disrupting the cell cycle and causing cell death. Approved originally for clinical use in Germany for cancer, the United States Food and Drug Administration approved bendamustine in 2008 for the treatment of indolent B-cell NHL that has progressed during or within six months of receiving rituximab (Rituxan) or a rituximab-containing regimen. It has also been approved to treat CLL/SLL.

Cortisteroids

  • Dexamethasone
  • Prednisone
  • Solumedrole

Biologic or Immunotherapy

Biologic therapy is the use of substances (made by the body or created in a laboratory) that are part of or stimulate the body's immune system to fight the cancer. This may be called immunotherapy. Monoclonal antibodies are produced to target certain receptors on the cancerous cells (antigens), and to destroy the cell. When a Y-shaped antibody attaches to such a target, it either alerts other cells of the immune system to destroy the cell, or its presence prompts the cell to die.

In the 1980's it became possible to genetically engineer antibodies to target a specific antigen and this eventually lead to the development of a new class of therapies. The three monoclonal antibody therapies are currently available for the treatment of CLL/SLL:

  • Ofatumumab (Arzerra) is another monoclonal antibody that targets the CD20 antigen, which is found on the surface of CLL cells. Unlike other monoclonal antibodies, ofatumumab (Arzerra) binds to a specific part of the CD20 protein on the surface of cells called the small loop epitope. This drug kills cells by recruiting proteins called "complement," that lead to cell death. It also induces antibody dependent cellular cytoxicity by recruiting the body's natural killing cells to kill CLL cells. The Food and Drug Administration (FDA) approved ofatumumab (Arzerra Injection, for intravenous infusion; GlaxoSmithKline) in combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL), for whom fludarabine-based therapy is considered inappropriate.
  • Obinutuzumab (GAZYVA, previously known as GA101) was approved the Food and Drug Administration (FDA) for its use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).
  • Rituximab (Rituxan) is a monoclonal antibody that targets a protein called CD20, which is found on the surface of cancerous and normal B-cells. The drug has already received approval (as a single agent or in combination with specific chemotherapies) for certain people with follicular lymphoma, diffuse large B-cell lymphoma or slow-growing B-cell NHL. Rituximab (Rituxan) has already been approved in Europe for the frontline treatment of CLL. Rituximab (Rituxan) was approved by the FDA in combination with fludarabine and cyclophosphamide for patients with untreated or previously treated CD20-positive chronic lymphocytic leukemia in February 2010. This treatment combination is referred to as FCR (fludarabine-cyclophosphamide-rituximab).

Targeted Therapy

Targeted therapies attack cancer cells in a more specific way than chemotherapy drugs. A better understanding of the biology and genetics of CLL/SLL is helping researchers identify specific molecules in lymphoma cells that may be good targets for new drugs. Most of these recently discovered molecules help control the growth and survival of lymphoma cells. The drugs that target these molecules are broadly called targeted or biologic therapies. These drugs may kill the lymphoma cells or slow down or stop their growth.

  • Ibrutinib (for patients with 17p deletions) - The Food and Drug Administration (FDA) expanded the approved use of ibrutinib (Imbruvica) to treat patients with chronic lymphocytic leukemia (CLL) who carry a deletion in chromosome 17 (17p deletion), which is associated with poor responses to standard treatment for CLL. Ibrutinib received a breakthrough therapy designation for this use.

Combination Therapy

In the past, patients were initially treated with either fludarabine alone or chlorambucil/prednisone and later switched to an alternative regimen if the initial treatment did not produce sufficient benefit. Current studies are showing that using several drugs together (combining fludarabine and cyclophosphamide) might be more effective.

Common drugs or combinations of drugs used as initial treatments for CLL/SLL include:

  • BR (bendamustine and rituximab)
  • CO (chlorambucil and obinutuzumab)
  • FCR (fludarabine, cyclophosphamide, and rituximab)
  • FR (fludarabine and rituximab)
  • Ibrutinib (for patients with 17p deletions)
  • Ofatumumab and chlorambucil
  • PCR (pentostatin, cyclophosphamide, and rituximab)

Radiation Therapy

Radiation therapy is the use of high-energy x-rays or other particles to kill cancer cells. Radiation therapy is not used frequently in patients with CLL because the disease is spread throughout the body. Radiation therapy can, however, be very helpful in shrinking an enlarged spleen or swollen lymph nodes and eliminating symptoms that may be associated with such growths. Radiation also has side effects previously quoted, such as immune suppression and penias.

Transplantation

Transplantation has not been routinely used with CLL/SLL patients. It does have some possible merit with patients who have transformed into a more aggressive disease. A typical transplant procedure uses chemotherapy and/or radiation to 'wipe out' the cell system in a patient. In autologous transplant, the patient's own cells are cleaned and re-introduced into the body. In allogeneic transplants, the patient receives a healthy product from a relative or a non-related matched donor. Both procedures carry considerable risk. In the allogeneic situation, there is the danger of rejection and associated disease.